Steroid hormone compositions and method of using same



United States Patent Ofifice 3,062,713 Patented Nov. 6, 1962 This invention relates to the therapeutic application of a new steroid, 17u-vinyl-5(10)-estren-17fi-ol-3-one (vinyl-estrenolone) both for humans and in veterinary medicine.

17oz-VlI1yl5(10)-6StrI1-17,B-Ol-3-OI16 is prepared as follows:

0.125 part of lithium in small pieces is added, little by little, to 100 parts of liquid ammonia in the presence of one crystal of ferric nitrate; a blue color develops, which disappears after about 20 minutes owing to the formation of the lithium-amide. A solution of 1 part of 3-methoxy-17a-ethynyl-1,3,5(10)-estratriene-17B-ol in 50 parts of anhydrous diethyl ether is then added over a period of 30 minutes, and the suspension is stirred for an additional 90 minutes; thereafter 1 part of lithium in small pieces is added over a period of about 20 minutes and stirring is continued for another 30 minutes. The resulting solution is then carefully treated with absolute ethanol over a period of 20 minutes, after which the ammonia is evaporated and the residue, diluted with water, is extracted with diethyl ether. The ethereal extract, washed with water and dried over sodium sulphate is evaporated to dryness.

The residue, dissolved in 90 parts of methanol, is treated for 40 minutes at 25 C. with 1.3 parts of bihydrated oxalic acid in 16.5 parts of water.

After diluting with Water, the solution is repeatedly extracted with diethyl ether, the combined extracts are washed with aqueous sodium bicarbonate followed by water, dried over sodium sulphate and evaporated to dryness. The crystallization of the residue from diethyl ether hexane is productive of 0.8 part of l7a-vinyl-5(10)- estrene-17fi-ol-3-one with a melting point of 142-143" C., an optical rotation of +161 (chloroform) and the analysis given below:

Found, percent: C, 79.86; H, 9.42. calcd.: C, 79.95; H, 9.39.

The drug has been resorted to in humans in the treatment of dysmenorrhea, menopausal disturbances, fecundation control in cases of hindered normal pregnancy (renal lesions, etc.); it has also been used in the case of women engaged in athletics when it would be advisable to delay their menstrual period.

Its anti-gonadotropic elfectiveness has proven to be very high as compared with similar compounds, and it has been found to be completely devoid of any undesirable side-effects.

In this regard the following tables show the pro-pregnancy efiectiveness of the present compound as compared 7 with progesterone and l7a-ethinyl-5(10)-estren-17fi-ol-3- one (ethinyl-estrenolone) in the Glauberg test its androgenic and assimilation effectiveness as determined by Heshbergers test in comparison with testosterone propionate and ethinylestrenolone, and its oestrogenous effectiveness as determined by Lausons test in comparison with oestradiol monobenzoate and ethinyl-estrenolone:

PRO-PREGNANCY EFFECTIVENESS OF VINYL-ESTRENOLONE Sub-cutaneous total dose Group and injec- No. Body McPhails table products ani- Weight, Rate mals g. Before treat. Treat.,

Control 2 920 Progesterone. 3 950 2.5 oestradiol..- 2 3+4+ Vinylestrenolone. 3 840 2.5 oestradiol... 2 1+1 Ethinylestrenol- 2 900 2.5 oestradiol... 2 1+1+ ANDROGENIC AND ASSIMILATION EFFECTIVE- NESS OF VINYL-ESTRENOLONE Body M. lev. Body W. M. Pros- Semin. ani. Groups and injeeweight after lev. tate, Vesi- Prosable products before treatani., mg. cles, tate tr., g. ment, mg. mg. Ther. g. Rate Castrated controls 35.3 49. 7 6.9 15. 3 6. 7 Testosterone propionate, 5007 35. 3 50.0 32. 0 101. 4 120. 6 0.29 Testosterone propionate, 35.0 47. 1 27. 4 98. 1 101. 1 0.24 Vinyl-estren. 500 35.0 43. 8 8. 1 13. 3 23. 1 Vinyl-estren., 100 35.0 41. 3 9.0 26. 9 25. 6 0. 18 Ethinylestrenolone,

VINYL-ESTRENOLONE OESTROGENOUS EFFECTIVENESS Initial Final Weight Weight Numbody body of of Group and injected product ber of Weight, weight, uterus, uterus,

rats g g. mg. 100

g.p.c.

Control 10. 0 35. 5. 49. 2 23. 7 48. 3 Oestradiol m.b.:

The data recorded in the tables show that the oestrogenous efiectiveness of the drug is very low, amounting to approximately /3 of that displayed by ethinyl-estrenolone. More over, as is the case with ethinyl-estrenolone, poor pro-pregnancy efficacy is shown and scarcely any androgenic and assimilative effect can be observed.

This undoubtedly results, especially in the therapeutic field, in a considerable advantage favoring the new steroid as compared with ethinyl-estrenolone, when one considers that the lower the side-effects are in an active compound, the more valuable it is for its intended specific use.

Clinical results.-Clinical experimentation has been EXAMPLE 1 carried out with vinyl-estrenolone in 52 women ranging in Tablets: 5 parts of vinyl-estrenolone are powdered age from 25 to 55 years, divided into groups as follows: finely so that it will pass a 120 mesh/ sq. cm. screen, then No. Posology Results cases daily Administr. Duration treated dosage, route in mgs. Positive Partial Negative Dysmeuorrhea. 18 2. 5-10 PeroralInject... 3 weeks after cessation 13 2 3 O IDBIISES. Pre-Menstrual Tension 14 2. 5-10 d -7daysbeioremenses..- 4 Menopausal Disturbances 20 10-40 0 20-30 days 2 3 As regards contraceptive effectiveness, the drug has mixed gradually with 103 parts lactose and 15 parts rice been tested in 4 women, three of whom suffered from starch. 15 parts of rice starch are suspended separately renal lesion and one with uterine malformation, at a 1n and heated with 150 parts of water to effect homogeposology of 5 to 10 mg. daily from the 5th to the 25th day, for three consecutive cycles, with favorable results neous distribution. The hot mixture is poured into the hormone-lactose-starch mixture and thoroughly kneaded.

in all four cases under consideration. The resulting production, then granulated and dried at For delay of menstruation in women engaged in athletic 50 C., granulated again and sieved through a 4-5 events: 5 mg. a day starting from 5 days before beginmesh/sq. cm. sieve. ning of menses up to 2 days before wanted menstrua- The sieved preparation is poured into amixer and there 1 is added 7.5 parts of magnesium stearate and 4 parts of Side-effects: Out of approximately 60 cases treated only talc. After 45 minutes, the preparation is transferred to 5% exhibited gastric intolerance and in no case was there a pressing-machine which manufactmes 150 mg. tablets observed any masculinizing effect from the use of the which have a diameter of 8 mm. and a central furrow. drug. Ampuls: 10 parts of vinyl-estrenolone are dissolved in Pharmaceuticalpreparations of the drug have been pro- 25 parts benzylbenzoate and 0.2 part chloretone with duced for intramuscular injection by dissolving the steroid heating and constant shaking. The mixture is then cooled in an oily vehicle such as teel oil, olive oil, oleic acid to room temperature and there is added sufiicient pure esters, and for oral administration by tabletting it in adolive oil, as used for sub-cutaneous injection, to bring to mixture with aninert carrier. 1000 parts. The mixture is filtered at a temperature of As exemplary of preparations designed for administra- 50 C. through filter paper to cause it to be absolutely tion by intramuscular injection, there may be mentioned clear.

The preparation is finally cooled to room temperature and poured into 1 cc. dose ampules. After sealing, the ampules are sterilized in an autoclave at -120 C.

The ratios set forth above may be varied in accordance with the posology previously mentioned. The present application is a continuation-in-part appli- As exemplary of tablets intended for oral admlmstracation of our application Ser. No. 736,458, filed May 20, tion, the following formulas are set forth: 1958, now Us, P t N 2,983,73 5,

1 cc. ampuls filled with 10 mg. of vinyl-estrenolone dissolved in olive oil and 2 cc. ampuls filled with 25 mg. of the drug dissolved in olive or similar pharmaceutically acceptable fatty oils.

Formula I We clam 1. A pharmaceutical composition in dosage unit form for intramuscular injection comprising from 2.5 to 40 mg. gmzlrestl'enolone 0g of 17a-vinyl-5(10)-estrenl7/8-ol-3-one together with a 058 non-toxic fatty oil. Rice f 30 2. A pharmaceutical composition in dosage unit form Magnesium steal'ate for oral administration comprising a tableted mixture of Talc from 2.5 to 40 mg. of 17a-vinyl-5(l0)-estren-17;3-ol-3- Formula II one and a non-toxic inert solid pharmaceutical carrier, said carrier being present in the major proportion. vmyl'estrenolone 3. A pharmaceutical composition in dosage unit form Lajctose 30 consisting of the following ingredients in approximately 322 22 3 Steamte 7 5 the amounts stated: Talc 4.5 17a-v1nyl-5(10)-estren-l7fl-ol-3-one 5 A pharmaceutical composition for veterinary use does Lactose 103 not differ materially from that meant for humans, with Rice starch 30 the exception of the steroid dosages. Examples of the Magnesium stear 7.5 most used veterinary compositions are set forth as fol- Talc 4,5 lows' 4. A pharmaceutical composition in dosage unit form Ampuls: 25 mg. in 2 cc. olive oil or other oily solvent. consisting of the following ingredients in approximately Tablets: the amounts stated: M

g, fggfg g I: 2 17a-vinyl-5(l0)-estren-l7fi-ol-3-one 10 Rice starch 3O 0 Lactose 98 Magnesium stearate 7.5 Rice Starch 30 1 45 Magnesium stearate 7.5 Talc 4.5

The following examples are set forth as being further exemplary of but not as limiting the present invention: 5. A therapeutic composition in dosage unit form com- 8,062,713 5 6 prising 10 mg. of 17a-viny1-5 (10)-estren-17;8-o1-3-one disfrom 2.5 mg. to 40 mg. of 17a-vinyl-5(10)-estren- 17,6-o1- solved in olive oil. 3-one.

6. A therapeutic composition in dosage unit form comprising 25 mg. of 17a-viny1-5(10)-estren-17fi-ol-3-one dis- Refe'ences c'ted m the file Patent solved in olive oil, 5 UNITED STATES PATENTS 7- A proc ss for conducting steroid therapy in a female 2,905,676 m Sept 22, 1959 Patient mprising a inistering daily to said patient 2 920 999 Agneno et 1 June 12, 1960 

1. A PHARMACEUTICAL COMPOSITION IN DOSAGE UNIT FORM FOR INTRAMUSCULAR INJECTION COMPRISING FROM 2.5 TO 40 MG. OF 17A-VINYL-5(10)-ESTREN-17B-OL-3-ONE TOGETHER WITH A NON-TOXIC FATTY OIL. 